The Experts below are selected from a list of 1863 Experts worldwide ranked by ideXlab platform
Suzanne Jackowski - One of the best experts on this subject based on the ideXlab platform.
-
Proposed Therapies for Pantothenate-Kinase-Associated Neurodegeneration.
Journal of experimental neuroscience, 2019Co-Authors: Suzanne JackowskiAbstract:Multiple approaches to therapy have been proposed for the rare inherited neurodegenerative disease associated with mutations in the PANK2 gene, called Pantothenate-Kinase-associated neurodegenerati...
-
Human Pantothenate Kinase 4 is a pseudo-Pantothenate Kinase.
Protein science : a publication of the Protein Society, 2019Co-Authors: Jiangwei Yao, Charles O. Rock, Chitra Subramanian, Suzanne JackowskiAbstract:Pantothenate Kinase generates 4'-phosphoPantothenate in the first and rate-determining step of coenzyme A (CoA) biosynthesis. The human genome encodes three well-characterized and nearly identical Pantothenate Kinases (PANK1-3) plus a putative bifunctional protein (PANK4) with a predicted amino-terminal Pantothenate Kinase domain fused to a carboxy-terminal phosphatase domain. Structural and phylogenetic analyses show that all active, characterized PANKs contain the key catalytic residues Glu138 and Arg207 (HsPANK3 numbering). However, all amniote PANK4s, including human PANK4, encode Glu138Val and Arg207Trp substitutions which are predicted to inactivate Kinase activity. Biochemical analysis corroborates bioinformatic predictions-human PANK4 lacks Pantothenate Kinase activity. Introducing Glu138Val and Arg207Trp substitutions to the human PANK3 and plant PANK4 abolished their robust Pantothenate Kinase activity. Introducing both catalytic residues back into human PANK4 restored Kinase activity, but only to a low level. This result suggests that epistatic changes to the rest of the protein already reduced the Kinase activity prior to mutation of the catalytic residues in the course of evolution. The PANK4 from frog, an anamniote living relative encoding the catalytically active residues, had only a low level of Kinase activity, supporting the view that HsPANK4 had reduced Kinase activity prior to the catalytic residue substitutions in amniotes. Together, our data show that human PANK4 is a pseudo-Pantothenate Kinase-a catalytically deficient variant of the catalytically active PANK4 found in plants and fungi. The Glu138Val and Arg207Trp substitutions in amniotes (HsPANK3 numbering) completely deactivated the Pantothenate Kinase activity that had already been reduced by prior epistatic mutations.
-
Proposed Therapies for Pantothenate-Kinase-Associated Neurodegeneration
SAGE Publishing, 2019Co-Authors: Suzanne JackowskiAbstract:Multiple approaches to therapy have been proposed for the rare inherited neurodegenerative disease associated with mutations in the PANK2 gene, called Pantothenate-Kinase-associated neurodegeneration (PKAN). Penetration of the blood-brain barrier for treatment of a central nervous system (CNS) disorder is a major challenge in drug discovery. Evaluation of the biochemistry and medicinal chemistry of the proposed therapies reveals potential liabilities among several compounds under consideration for clinical development
-
A therapeutic approach to Pantothenate Kinase associated neurodegeneration.
Nature communications, 2018Co-Authors: Lalit Kumar Sharma, Charles O. Rock, Matthew W. Frank, Chitra Subramanian, Mi-kyung Yun, Stephen W. White, Richard E. Lee, Suzanne JackowskiAbstract:Pantothenate Kinase (PANK) is a metabolic enzyme that regulates cellular coenzyme A (CoA) levels. There are three human PANK genes, and inactivating mutations in PANK2 lead to Pantothenate Kinase associated neurodegeneration (PKAN). Here we performed a library screen followed by chemical optimization to produce PZ-2891, an allosteric PANK activator that crosses the blood brain barrier. PZ-2891 occupies the Pantothenate pocket and engages the dimer interface to form a PANK•ATP•Mg2+•PZ-2891 complex. The binding of PZ-2891 to one protomer locks the opposite protomer in a catalytically active conformation that is refractory to acetyl-CoA inhibition. Oral administration of PZ-2891 increases CoA levels in mouse liver and brain. A knockout mouse model of brain CoA deficiency exhibited weight loss, severe locomotor impairment and early death. Knockout mice on PZ-2891 therapy gain weight, and have improved locomotor activity and life span establishing pantazines as novel therapeutics for the treatment of PKAN.
-
A therapeutic approach to Pantothenate Kinase associated neurodegeneration
Nature Communications, 2018Co-Authors: Lalit Kumar Sharma, Charles O. Rock, Matthew W. Frank, Chitra Subramanian, Mi-kyung Yun, Stephen W. White, Richard E. Lee, Suzanne JackowskiAbstract:Pantothenate Kinase (PANK) is a metabolic enzyme that regulates cellular coenzyme A (CoA) levels. There are three human PANK genes, and inactivating mutations in PANK2 lead to Pantothenate Kinase associated neurodegeneration (PKAN). Here we performed a library screen followed by chemical optimization to produce PZ-2891, an allosteric PANK activator that crosses the blood brain barrier. PZ-2891 occupies the Pantothenate pocket and engages the dimer interface to form a PANK•ATP•Mg^2+•PZ-2891 complex. The binding of PZ-2891 to one protomer locks the opposite protomer in a catalytically active conformation that is refractory to acetyl-CoA inhibition. Oral administration of PZ-2891 increases CoA levels in mouse liver and brain. A knockout mouse model of brain CoA deficiency exhibited weight loss, severe locomotor impairment and early death. Knockout mice on PZ-2891 therapy gain weight, and have improved locomotor activity and life span establishing pantazines as novel therapeutics for the treatment of PKAN. Mutations in pantotenate Kinase (PANK) cause neurodegneration. Here the authors carry out achemical screen and identify a PANK activator that is orally available, crosses the blood brain barrierand show that it effecttive in improving pathology and life span in a mouse model of the disease.
Charles O. Rock - One of the best experts on this subject based on the ideXlab platform.
-
Human Pantothenate Kinase 4 is a pseudo-Pantothenate Kinase.
Protein science : a publication of the Protein Society, 2019Co-Authors: Jiangwei Yao, Charles O. Rock, Chitra Subramanian, Suzanne JackowskiAbstract:Pantothenate Kinase generates 4'-phosphoPantothenate in the first and rate-determining step of coenzyme A (CoA) biosynthesis. The human genome encodes three well-characterized and nearly identical Pantothenate Kinases (PANK1-3) plus a putative bifunctional protein (PANK4) with a predicted amino-terminal Pantothenate Kinase domain fused to a carboxy-terminal phosphatase domain. Structural and phylogenetic analyses show that all active, characterized PANKs contain the key catalytic residues Glu138 and Arg207 (HsPANK3 numbering). However, all amniote PANK4s, including human PANK4, encode Glu138Val and Arg207Trp substitutions which are predicted to inactivate Kinase activity. Biochemical analysis corroborates bioinformatic predictions-human PANK4 lacks Pantothenate Kinase activity. Introducing Glu138Val and Arg207Trp substitutions to the human PANK3 and plant PANK4 abolished their robust Pantothenate Kinase activity. Introducing both catalytic residues back into human PANK4 restored Kinase activity, but only to a low level. This result suggests that epistatic changes to the rest of the protein already reduced the Kinase activity prior to mutation of the catalytic residues in the course of evolution. The PANK4 from frog, an anamniote living relative encoding the catalytically active residues, had only a low level of Kinase activity, supporting the view that HsPANK4 had reduced Kinase activity prior to the catalytic residue substitutions in amniotes. Together, our data show that human PANK4 is a pseudo-Pantothenate Kinase-a catalytically deficient variant of the catalytically active PANK4 found in plants and fungi. The Glu138Val and Arg207Trp substitutions in amniotes (HsPANK3 numbering) completely deactivated the Pantothenate Kinase activity that had already been reduced by prior epistatic mutations.
-
A therapeutic approach to Pantothenate Kinase associated neurodegeneration.
Nature communications, 2018Co-Authors: Lalit Kumar Sharma, Charles O. Rock, Matthew W. Frank, Chitra Subramanian, Mi-kyung Yun, Stephen W. White, Richard E. Lee, Suzanne JackowskiAbstract:Pantothenate Kinase (PANK) is a metabolic enzyme that regulates cellular coenzyme A (CoA) levels. There are three human PANK genes, and inactivating mutations in PANK2 lead to Pantothenate Kinase associated neurodegeneration (PKAN). Here we performed a library screen followed by chemical optimization to produce PZ-2891, an allosteric PANK activator that crosses the blood brain barrier. PZ-2891 occupies the Pantothenate pocket and engages the dimer interface to form a PANK•ATP•Mg2+•PZ-2891 complex. The binding of PZ-2891 to one protomer locks the opposite protomer in a catalytically active conformation that is refractory to acetyl-CoA inhibition. Oral administration of PZ-2891 increases CoA levels in mouse liver and brain. A knockout mouse model of brain CoA deficiency exhibited weight loss, severe locomotor impairment and early death. Knockout mice on PZ-2891 therapy gain weight, and have improved locomotor activity and life span establishing pantazines as novel therapeutics for the treatment of PKAN.
-
A therapeutic approach to Pantothenate Kinase associated neurodegeneration
Nature Communications, 2018Co-Authors: Lalit Kumar Sharma, Charles O. Rock, Matthew W. Frank, Chitra Subramanian, Mi-kyung Yun, Stephen W. White, Richard E. Lee, Suzanne JackowskiAbstract:Pantothenate Kinase (PANK) is a metabolic enzyme that regulates cellular coenzyme A (CoA) levels. There are three human PANK genes, and inactivating mutations in PANK2 lead to Pantothenate Kinase associated neurodegeneration (PKAN). Here we performed a library screen followed by chemical optimization to produce PZ-2891, an allosteric PANK activator that crosses the blood brain barrier. PZ-2891 occupies the Pantothenate pocket and engages the dimer interface to form a PANK•ATP•Mg^2+•PZ-2891 complex. The binding of PZ-2891 to one protomer locks the opposite protomer in a catalytically active conformation that is refractory to acetyl-CoA inhibition. Oral administration of PZ-2891 increases CoA levels in mouse liver and brain. A knockout mouse model of brain CoA deficiency exhibited weight loss, severe locomotor impairment and early death. Knockout mice on PZ-2891 therapy gain weight, and have improved locomotor activity and life span establishing pantazines as novel therapeutics for the treatment of PKAN. Mutations in pantotenate Kinase (PANK) cause neurodegneration. Here the authors carry out achemical screen and identify a PANK activator that is orally available, crosses the blood brain barrierand show that it effecttive in improving pathology and life span in a mouse model of the disease.
-
Correction of a genetic deficiency in Pantothenate Kinase 1 using phosphoPantothenate replacement therapy.
Molecular genetics and metabolism, 2015Co-Authors: Stephen P. Zano, Charles O. Rock, Caroline Pate, Matthew W. Frank, Suzanne JackowskiAbstract:Coenzyme A (CoA) is a ubiquitous cofactor involved in numerous essential biochemical transformations, and along with its thioesters is a key regulator of intermediary metabolism. Pantothenate (vitamin B5) phosphorylation by Pantothenate Kinase (PanK) is thought to control the rate of CoA production. Pantothenate Kinase associated neurodegeneration is a hereditary disease that arises from mutations that inactivate the human PANK2 gene. Aryl phosphoramidate phosphoPantothenate derivatives were prepared to test the feasibility of using phosphoPantothenate replacement therapy to bypass the genetic deficiency in the Pank1(-/-) mouse model. The efficacies of candidate compounds were first compared by measuring the ability to increase CoA levels in Pank1(-/-) mouse embryo fibroblasts. Administration of selected candidate compounds to Pank1(-/-) mice corrected their deficiency in hepatic CoA. The PanK bypass was confirmed by the incorporation of intact phosphoPantothenate into CoA using triple-isotopically labeled compound. These results provide strong support for PanK as a master regulator of intracellular CoA and illustrate the feasibility of employing PanK bypass therapy to restore CoA levels in genetically deficient mice.
-
Localization and regulation of mouse Pantothenate Kinase 2
FEBS letters, 2007Co-Authors: Roberta Leonardi, Yong-mei Zhang, Charles O. Rock, Athanasios Lykidis, Suzanne JackowskiAbstract:Coenzyme A (CoA) biosynthesis is initiated by Pantothenate Kinase (PanK) and CoA levels are controlled through differential expression and feedback regulation of PanK isoforms. PanK2 is a mitochondrial protein in humans, but comparative genomics revealed that acquisition of a mitochondrial targeting signal was limited to primates. Human and mouse PanK2 possessed similar biochemical properties, with inhibition by acetyl-CoA and activation by palmitoylcarnitine. Mouse PanK2 localized in the cytosol, and the expression of PanK2 was higher in human brain compared to mouse brain. Differences in expression and subcellular localization should be considered in developing a mouse model for human PanK2 deficiency.
Alfonso Fasano - One of the best experts on this subject based on the ideXlab platform.
-
Tongue Protrusion Dystonia in Pantothenate Kinase-Associated Neurodegeneration.
Pediatric neurology, 2019Co-Authors: Yasaman Saeedi, Anthony E. Lang, Alfonso Fasano, Foad Kazemi, Seyed Amir Hassan Habibi, Abbas Tafakhori, Ahmad Chitsaz, Mohammad RohaniAbstract:Abstract Background Tongue protrusion dystonia is an uncommon focal dystonia involving the lingual muscles. Causes of tongue protrusion dystonia include tardive dystonia, posthypoxic dystonia, neuroacanthocytosis, Pantothenate Kinase-associated neurodegeneration, and Lesch-Nyhan syndrome. Method We summarize three children with Pantothenate Kinase-associated neurodegeneration and tongue protrusion dystonia. All three patients underwent careful neurological examination, brain magnetic resonance imaging, and genetic testing. Results Tongue protrusion dystonia was a prominent and disabling symptom in all three patients. Brain magnetic resonance imaging revealed a typical eye of the tiger sign in all patients. Two patients had the same genetic mutation (c.1168 A>T mutation, p.I390F). Conclusions Tongue protrusion dystonia may be a clue to the underlying etiology of dystonia, including hereditary forms of dystonia. Among them, Pantothenate Kinase-associated neurodegeneration is an important cause, especially in children.
-
Deep brain stimulation for Pantothenate Kinase-associated neurodegeneration: A meta-analysis.
Movement disorders : official journal of the Movement Disorder Society, 2019Co-Authors: Philippe De Vloo, Mohammad Rohani, Alfonso Fasano, Darrin J. Lee, Robert F. Dallapiazza, Renato P. Munhoz, George M. Ibrahim, Mojgan Hodaie, Andres M. Lozano, Suneil K. KaliaAbstract:BACKGROUND Pantothenate Kinase-associated neurodegeneration is a rare autosomal-recessive disorder, characterized by progressive neurodegeneration associated with brain iron accumulation. DBS has been trialed to treat related movement disorders, particularly dystonia. The objective of this study was to determine the outcome and safety of DBS for Pantothenate Kinase-associated neurodegeneration. METHODS We performed a meta-analysis using independent participant data (n = 99) from 38 articles. Primary outcome was change in movement and disability scores of the Burke-Fahn-Marsden Dystonia Rating Scale 1 year postoperatively. Secondary outcomes were response rate and complications. RESULTS Patients with classic-type (n = 58) and atypical-type (n = 15) Pantothenate Kinase-associated neurodegeneration were operated on at a median age of 11 and 31 years, respectively (P 1 year following GPi-DBS or with other DBS targets. Overall, small sample sizes limited generalizability. CONCLUSIONS This meta-analysis provides level 4 evidence that GPi-DBS for Pantothenate Kinase-associated neurodegeneration may improve dystonia movement scores in classic type and atypical type and disability scores in atypical type 1 year postoperatively. © 2019 International Parkinson and Movement Disorder Society.
-
tremor dominant Pantothenate Kinase associated neurodegeneration
Movement Disorders Clinical Practice, 2017Co-Authors: Mohammad Rohani, Afagh Alavi, Gholam Ali Shahidi, Anthony E. Lang, Niloufar Yousefi, Said Razme, Alfonso FasanoAbstract:Background Neurodegeneration with brain iron accumulation (NBIA) includes rare and heterogeneous group of disorders characterized by iron deposition in the basal ganglia. Pantothenate Kinase-associated neurodegeneration (PKAN), is the most common NBIA and has two main presentations: typical and atypical, the latter rarely presenting with tremor. Method Reported patients underwent full neurologic examination, a standard brain MRI and genetic testing for PKAN. Results Three cases of ‘tremor-dominant’ PKAN with a relatively benign course were reported: dystonic tremor was seen in one patient and Parkinsonian tremor in remaining ones. All of them had homozygous mutations in PANK2 gene and typical eye of the tiger sign on brain MRI. Conclusions PKAN (and NBIA in general) might be a potential cause of tremor, thus emphasizing the need to consider this diagnosis even in patients with a clinical diagnosis of essential, dystonic or Parkinsonian tremor. This article is protected by copyright. All rights reserved.
-
Tremor‐Dominant Pantothenate Kinase‐associated Neurodegeneration
Movement disorders clinical practice, 2017Co-Authors: Mohammad Rohani, Afagh Alavi, Gholam Ali Shahidi, Anthony E. Lang, Niloufar Yousefi, Said Razme, Alfonso FasanoAbstract:Background Neurodegeneration with brain iron accumulation (NBIA) includes rare and heterogeneous group of disorders characterized by iron deposition in the basal ganglia. Pantothenate Kinase-associated neurodegeneration (PKAN), is the most common NBIA and has two main presentations: typical and atypical, the latter rarely presenting with tremor. Method Reported patients underwent full neurologic examination, a standard brain MRI and genetic testing for PKAN. Results Three cases of ‘tremor-dominant’ PKAN with a relatively benign course were reported: dystonic tremor was seen in one patient and Parkinsonian tremor in remaining ones. All of them had homozygous mutations in PANK2 gene and typical eye of the tiger sign on brain MRI. Conclusions PKAN (and NBIA in general) might be a potential cause of tremor, thus emphasizing the need to consider this diagnosis even in patients with a clinical diagnosis of essential, dystonic or Parkinsonian tremor. This article is protected by copyright. All rights reserved.
Mohammad Rohani - One of the best experts on this subject based on the ideXlab platform.
-
Tongue Protrusion Dystonia in Pantothenate Kinase-Associated Neurodegeneration.
Pediatric neurology, 2019Co-Authors: Yasaman Saeedi, Anthony E. Lang, Alfonso Fasano, Foad Kazemi, Seyed Amir Hassan Habibi, Abbas Tafakhori, Ahmad Chitsaz, Mohammad RohaniAbstract:Abstract Background Tongue protrusion dystonia is an uncommon focal dystonia involving the lingual muscles. Causes of tongue protrusion dystonia include tardive dystonia, posthypoxic dystonia, neuroacanthocytosis, Pantothenate Kinase-associated neurodegeneration, and Lesch-Nyhan syndrome. Method We summarize three children with Pantothenate Kinase-associated neurodegeneration and tongue protrusion dystonia. All three patients underwent careful neurological examination, brain magnetic resonance imaging, and genetic testing. Results Tongue protrusion dystonia was a prominent and disabling symptom in all three patients. Brain magnetic resonance imaging revealed a typical eye of the tiger sign in all patients. Two patients had the same genetic mutation (c.1168 A>T mutation, p.I390F). Conclusions Tongue protrusion dystonia may be a clue to the underlying etiology of dystonia, including hereditary forms of dystonia. Among them, Pantothenate Kinase-associated neurodegeneration is an important cause, especially in children.
-
A novel homozygous variation in the PANK2 gene in two Persian siblings with atypical Pantothenate Kinase associated neurodegeneration.
Neurology international, 2019Co-Authors: Amir Hasan Habibi, Saeed Razmeh, Omid Aryani, Mohammad Rohani, Laleh Taghavian, Elham Alizadeh, Karim Moradian Kokhedan, Maryam ZaribafianAbstract:Pantothenate Kinase-associated Neurodegeneration (PKAN) is an autosomal recessive disorder that is caused by variation in Pantothenate Kinase-2 gene (PANK2) gene on chromosome 20. The common presentation of this disease includes progressive dystonia, Parkinsonism, retinopathy, cognitive impairment, and spasticity. The typical magnetic resonance imaging finding is eye of the tiger sign in globus pallidus and not pathogenic and not found in all patients. In the present study, we describe two siblings who have a novel variation of the PANK2 gene. These patients with the same genotype, have different ages at the onset of disease and also the various severity of the disease. The description of these cases helps to understand this disease, its symptoms, pathogenesis, and its treatment.
-
Deep brain stimulation for Pantothenate Kinase-associated neurodegeneration: A meta-analysis.
Movement disorders : official journal of the Movement Disorder Society, 2019Co-Authors: Philippe De Vloo, Mohammad Rohani, Alfonso Fasano, Darrin J. Lee, Robert F. Dallapiazza, Renato P. Munhoz, George M. Ibrahim, Mojgan Hodaie, Andres M. Lozano, Suneil K. KaliaAbstract:BACKGROUND Pantothenate Kinase-associated neurodegeneration is a rare autosomal-recessive disorder, characterized by progressive neurodegeneration associated with brain iron accumulation. DBS has been trialed to treat related movement disorders, particularly dystonia. The objective of this study was to determine the outcome and safety of DBS for Pantothenate Kinase-associated neurodegeneration. METHODS We performed a meta-analysis using independent participant data (n = 99) from 38 articles. Primary outcome was change in movement and disability scores of the Burke-Fahn-Marsden Dystonia Rating Scale 1 year postoperatively. Secondary outcomes were response rate and complications. RESULTS Patients with classic-type (n = 58) and atypical-type (n = 15) Pantothenate Kinase-associated neurodegeneration were operated on at a median age of 11 and 31 years, respectively (P 1 year following GPi-DBS or with other DBS targets. Overall, small sample sizes limited generalizability. CONCLUSIONS This meta-analysis provides level 4 evidence that GPi-DBS for Pantothenate Kinase-associated neurodegeneration may improve dystonia movement scores in classic type and atypical type and disability scores in atypical type 1 year postoperatively. © 2019 International Parkinson and Movement Disorder Society.
-
tremor dominant Pantothenate Kinase associated neurodegeneration
Movement Disorders Clinical Practice, 2017Co-Authors: Mohammad Rohani, Afagh Alavi, Gholam Ali Shahidi, Anthony E. Lang, Niloufar Yousefi, Said Razme, Alfonso FasanoAbstract:Background Neurodegeneration with brain iron accumulation (NBIA) includes rare and heterogeneous group of disorders characterized by iron deposition in the basal ganglia. Pantothenate Kinase-associated neurodegeneration (PKAN), is the most common NBIA and has two main presentations: typical and atypical, the latter rarely presenting with tremor. Method Reported patients underwent full neurologic examination, a standard brain MRI and genetic testing for PKAN. Results Three cases of ‘tremor-dominant’ PKAN with a relatively benign course were reported: dystonic tremor was seen in one patient and Parkinsonian tremor in remaining ones. All of them had homozygous mutations in PANK2 gene and typical eye of the tiger sign on brain MRI. Conclusions PKAN (and NBIA in general) might be a potential cause of tremor, thus emphasizing the need to consider this diagnosis even in patients with a clinical diagnosis of essential, dystonic or Parkinsonian tremor. This article is protected by copyright. All rights reserved.
-
Tremor‐Dominant Pantothenate Kinase‐associated Neurodegeneration
Movement disorders clinical practice, 2017Co-Authors: Mohammad Rohani, Afagh Alavi, Gholam Ali Shahidi, Anthony E. Lang, Niloufar Yousefi, Said Razme, Alfonso FasanoAbstract:Background Neurodegeneration with brain iron accumulation (NBIA) includes rare and heterogeneous group of disorders characterized by iron deposition in the basal ganglia. Pantothenate Kinase-associated neurodegeneration (PKAN), is the most common NBIA and has two main presentations: typical and atypical, the latter rarely presenting with tremor. Method Reported patients underwent full neurologic examination, a standard brain MRI and genetic testing for PKAN. Results Three cases of ‘tremor-dominant’ PKAN with a relatively benign course were reported: dystonic tremor was seen in one patient and Parkinsonian tremor in remaining ones. All of them had homozygous mutations in PANK2 gene and typical eye of the tiger sign on brain MRI. Conclusions PKAN (and NBIA in general) might be a potential cause of tremor, thus emphasizing the need to consider this diagnosis even in patients with a clinical diagnosis of essential, dystonic or Parkinsonian tremor. This article is protected by copyright. All rights reserved.
Susan J. Hayflick - One of the best experts on this subject based on the ideXlab platform.
-
looking deep into the eye of the tiger in Pantothenate Kinase associated neurodegeneration
American Journal of Neuroradiology, 2018Co-Authors: Jae-hyeok Lee, Allison Gregory, P. Hogarth, Caleb Rogers, Susan J. HayflickAbstract:BACKGROUND AND PURPOSE: A detailed delineation of the MR imaging changes in the globus pallidus in Pantothenate Kinase–associated neurodegeneration will be helpful for diagnosis and monitoring of patients. The aim of this study was to determine the morphologic spectrum of the “eye-of-the-tiger” sign and the topographic pattern of iron deposition in a group of patients with Pantothenate Kinase–associated neurodegeneration. MATERIALS AND METHODS: Seventy-four MR imaging scans from 54 individuals with PANK2 mutations were analyzed for signal patterns in the globus pallidus. Sixteen SWI data from 15 patients who underwent 1.5T ( n = 7), 3T ( n = 7), and 7T ( n = 2) MR imaging were included to visualize the iron topography. RESULTS: The linear hyperintensity alongside the medial border of the globus pallidus was the earliest T2 signal change. This finding was evident before SWI changes from iron deposition became visible. T2WI performed in early childhood mostly showed isolated hyperintense signal. In adult patients, marked signal reduction within an earlier hyperintense center resulting from iron accumulation led to the loss of signal difference between the central and surrounding areas. Signal hypointensity on SWI progressed from the medial to the lateral portion of the globus pallidus with increasing age. The fiber connections between the medial globus pallidus and the anteromedial aspect of the substantia nigra and subthalamic nucleus were markedly hypointense on SWI. CONCLUSIONS: In Pantothenate Kinase–associated neurodegeneration, the globus pallidus MR imaging changes using SWI develop as region-specific and age-dependent phenomena. Signal inhomogeneity was observed across the globus pallidus in Pantothenate Kinase–associated neurodegeneration and should be considered when determining the concentration of iron.
-
Looking Deep into the Eye-of-the-Tiger in Pantothenate Kinase–Associated Neurodegeneration
AJNR. American journal of neuroradiology, 2018Co-Authors: Jae-hyeok Lee, Allison Gregory, P. Hogarth, Caleb Rogers, Susan J. HayflickAbstract:BACKGROUND AND PURPOSE: A detailed delineation of the MR imaging changes in the globus pallidus in Pantothenate Kinase–associated neurodegeneration will be helpful for diagnosis and monitoring of patients. The aim of this study was to determine the morphologic spectrum of the “eye-of-the-tiger” sign and the topographic pattern of iron deposition in a group of patients with Pantothenate Kinase–associated neurodegeneration. MATERIALS AND METHODS: Seventy-four MR imaging scans from 54 individuals with PANK2 mutations were analyzed for signal patterns in the globus pallidus. Sixteen SWI data from 15 patients who underwent 1.5T ( n = 7), 3T ( n = 7), and 7T ( n = 2) MR imaging were included to visualize the iron topography. RESULTS: The linear hyperintensity alongside the medial border of the globus pallidus was the earliest T2 signal change. This finding was evident before SWI changes from iron deposition became visible. T2WI performed in early childhood mostly showed isolated hyperintense signal. In adult patients, marked signal reduction within an earlier hyperintense center resulting from iron accumulation led to the loss of signal difference between the central and surrounding areas. Signal hypointensity on SWI progressed from the medial to the lateral portion of the globus pallidus with increasing age. The fiber connections between the medial globus pallidus and the anteromedial aspect of the substantia nigra and subthalamic nucleus were markedly hypointense on SWI. CONCLUSIONS: In Pantothenate Kinase–associated neurodegeneration, the globus pallidus MR imaging changes using SWI develop as region-specific and age-dependent phenomena. Signal inhomogeneity was observed across the globus pallidus in Pantothenate Kinase–associated neurodegeneration and should be considered when determining the concentration of iron.
-
Metabolism and energy requirements in Pantothenate Kinase-associated neurodegeneration
Molecular genetics and metabolism, 2013Co-Authors: Sarah M. Williams, Susan J. Hayflick, Allison Gregory, P. Hogarth, Melanie B. GillinghamAbstract:Pantothenate Kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder of coenzyme A homeostasis caused by defects in the mitochondrial Pantothenate Kinase 2. Patients with PKAN present with a progressive neurological decline and brain iron accumulation, but general energy balance and nutrition status among these patients has not been reported. To determine if defects in PANK2 change basic energy metabolism in humans, we measured body composition, resting energy expenditure, dietary intake, and blood metabolites among 16 subjects with PKAN. Subjects had a broad range of disease severity but, despite the essential role of coenzyme A in energy metabolism, the subjects had remarkably normal body composition, dietary intake and energy metabolism compared to population normal values. We did observe increased resting energy expenditure associated with disease severity, suggesting increased energy needs later in the disease process, and elevated urinary mevalonate levels.
-
Novel histopathologic findings in molecularly-confirmed Pantothenate Kinase-associated neurodegeneration
Brain, 2011Co-Authors: Michael C. Kruer, Susan J. Hayflick, Alessandro Malandrini, Mark Hiken, Allison Gregory, David Clark, P. Hogarth, Marjorie R. Grafe, Randall L. WoltjerAbstract:Pantothenate Kinase-associated neurodegeneration is a form of neurodegeneration with brain iron accumulation, characterized by a progressive movement disorder and prominent iron deposition in the globus pallidus. Formerly referred to as Hallervorden–Spatz syndrome, the disorder was renamed Pantothenate Kinase-associated neurodegeneration after discovery of the causative gene, PANK2. Although the pathological features of clinically characterized Hallervorden–Spatz syndrome have been described, the literature is confounded by the historical use of this term for nearly all conditions with prominent basal ganglia iron accumulation and by the fact that this term encompasses a genetically heterogeneous group of disorders, now referred to as ‘neurodegeneration with brain iron accumulation’. As a result, interpreting reports that precede molecular characterization of specific forms of neurodegeneration with brain iron accumulation is problematic. In the present studies, we describe neuropathological findings in six cases of molecularly confirmed Pantothenate Kinase-associated neurodegeneration. We identify prominent ubiquinated deposits in Pantothenate Kinase-associated neurodegeneration. We also characterize two distinct origins of spheroid bodies and delineate histological features of iron deposition. In so doing, we characterize fundamental features of the disease and redefine its nosological relationship to other neurodegenerative disorders.
-
discordant expression of mir 103 7 and Pantothenate Kinase host genes in mouse
Molecular Genetics and Metabolism, 2010Co-Authors: Brenda J Polster, Shawn K. Westaway, Thuy M Nguyen, Moon Y Yoon, Susan J. HayflickAbstract:miR-103 and miR-107, microRNAs hosted by Pantothenate Kinase genes, are proposed to regulate cellular lipid metabolism. microRNA-mediated regulation is complex, potentially affecting expression of the host gene, related enzymes within the same pathway, or apparently distinct targets. Using qRT-PCR, we demonstrate that miR-103 and miR-107 expression does not correlate with expression of host Pantothenate Kinase genes in mouse tissues. The miR-103/7 family thus provides an intriguing model for dissecting microRNA transcription, processing and coordinated function within host genes.
